KR20130085406A - 2-amino-pyrimidine derivatives useful as inhibitors of jnk - Google Patents

Abstract

상기 식에서,
R⁵는 하기 화학식 a 또는 b의 기이고:
화학식 a

화학식 b

m, n, p, q, X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ 및 R⁹는 본원에 기재된 바와 같다. The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds and compositions disclosed herein are useful for modulating the activity of JNK and for treating diseases associated with JNK activity:
Formula I

In this formula,
R ⁵ is a group of formula a or b:
A

Formula b

m, n, p, q, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as described herein.

Description

2-amino-pyrimidine derivatives useful as JNK inhibitors {2-AMINO-PYRIMIDINE DERIVATIVES USEFUL AS INHIBITORS OF JNK}

The present invention relates generally to the field of treatment of pharmacological and inflammatory disorders. More specifically, the present invention relates to prodrugs of JNK inhibitors, methods of making such inhibitors, and corresponding methods, formulations and compositions for inhibiting JNK and treating JNK-mediated disorders.

c-Jun N-terminal kinase (JNK), along with p38 and extracellular signal-regulated kinase (ERK), is a member of the mitogen-activated protein kinase family. Three different genes (jnk1, jnk2 and jnk3) encoding ten splice variants have been identified. JNK1 and JNK2 are expressed in a variety of tissues, while JNK3 is mainly expressed in neurons, and to a lesser extent in the heart and testes. Members of the JNK lineage are activated by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), and ambient stress. Activation of JNK is mediated by its upstream kinases MKK4 and MKK7 via the double phosphorylation of Thr-183 and Tyr-185. It has been suggested that MKK4 and MKK7 can be activated by various upstream kinases including MEKK1 and MEKK4, depending on external stimuli and cellular environment. Specificity of JNK signaling is achieved by using a framework protein called JNK-interacting protein to form a JNK-specific signaling complex containing complex components of multistage kinase. JNK is inflamed by phosphorylation of certain substrates, including transcription factors such as c-Jun, components of the activator protein-1 (AP1) family and ATF2 and non-transcription factors such as IRS-1 and Bc1-2, T It has been shown to play an important role in cell function, apotosis and cell survival. Over-activation of JNK is considered an important mechanism in autoimmunity, inflammatory, metabolic, neurological diseases and cancer.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints. In addition to joint edema and pain caused by the inflammatory process, ultimately debilitating joint damage and deformation develops in most RA patients. Several lines of noteworthy pharmacological and genetic evidence in cellular and animal models strongly suggest the relevance and importance of activated JNK in the pathogenesis of RA. First, abnormal activation of JNK was detected in both human arthritis joints from RA patients and in rodent arthritis joints from animal models of arthritis. In addition, inhibition of JNK activation by selective JNK inhibitors blocked pro-inflammatory cytokines and MMP production in human synovial cells, macrophages and lymphocytes. Importantly, administration of selective JNK inhibitors in rats with osteoarthritis or in mice with collagen-induced arthritis effectively protects the joints from destruction by inhibiting cytokine and collagenase expression and prevents foot edema. Significantly reduced.

Asthma is a chronic inflammatory disease of the airways, characterized by the presence of inflammatory processes in the cells and bronchial hypersensitivity associated with structural changes in the airways. Such disorders are suggested to be induced by a number of cell types in the airways, including T lymphocytes, eosinophils, mast cells, neutrophils and epithelial cells. Based on recent proof-of-concept studies, JNK has proven to be a promising treatment for asthma. JNK inhibitors have been shown to significantly block RANTES production in activated human airway smooth cells. More importantly, JNK inhibitors have shown excellent efficacy on their ability to reduce cell infiltration, inflammation, hypersensitivity, smooth muscle proliferation and IgE production in chronic rat and mouse models. This observation suggests an important role of JNK in allergic inflammation, a process of airway remodeling associated with hypersensitivity. Thus, blocking JNK activity is expected to be beneficial for the treatment of asthma.

Type 2 diabetes is the most serious and widespread metabolic disease characterized by insulin resistance and insulin secretion disorders as a result of abnormal lipid metabolism associated with chronic low levels of inflammation and oxidative stress. JNK activity is reported to be abnormally elevated in various diabetic target tissues under obese and diabetic conditions. Activation of the JNK pathway by pro-inflammatory cytokines and oxidative stress negatively regulates insulin signaling through phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser ³⁰⁷ , thus contributing to insulin resistance and glucose tolerance do. Strong genetic evidence has been presented from clear animal model studies using jnk ^{− / −} mice crossed with genetic (ob / ob) obese mice or dietary obese mice. Loss (JNK2 ^{- / -)} loss of function of JNK2 ^{(- / -} JNK1) of, JNK1 features non-obese mice were protected from weight gain, increased steady-state levels of blood glucose, and reduced plasma insulin levels. These studies demonstrated the potential utility of JNK inhibitors in the treatment of obesity / type 2 diabetes.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and stroke are central nervous system (CNS) diseases characterized by synaptic loss, neuronal atrophy and death. The JNK pathway leading to c-Jun activation has been shown to play a causal role in the induction of various stimuli in the apoptosis of isolated primary embryonic neurons and complex neuronal cell lines. Over-activation of JNK has been observed in the human brain from AD patients or in rodent brain sections derived from animal models of neurodegenerative diseases. For example, increased phospho-JNK was detected in post-mortem brains from AD patients. Administration of JNK inhibitory peptide (JIP-1 peptide) in a rodent model of AD induced by β-amyloid peptide administration prevented synaptic plasticity disorders. In the animal model of PD (MPTP model), elevated phospho-MKK4 and phospho-JNK were observed simultaneously with neuronal cell death. Adenovirus gene transfer of a JNK inhibitory peptide (JIP-1 peptide) to the striatum of mice inhibits MPTP-mediated JNK, c-Jun and caspase activation, thus preventing neuronal cell death in melanoma Thereby weakening behavioral disorders. In addition, in animal models of ischemic stroke induced by glutamate excitatory toxicity, mice lacking JNK3, but not JNK1 or JNK2, were resistant to carboxylic acid (glutamate receptor agonist) -mediated seizures or neuronal death. These data suggest that JNK3 is a major cause of glutamate excitatory toxicity, an important factor in the ischemic state. In sum, the data suggest that JNK is an interesting target for multiple CNS diseases associated with neuronal cell death.

Together with deregulated angiogenesis, uncontrolled cell growth, proliferation and migration leads to the formation of malignant tumors. The JNK signaling pathway cannot act exclusively in apoptosis, and sustained JNK activation leading to AP1 activation has recently been believed to contribute to the survival of cells of certain cancer types, such as glioblastoma and BCL-ABL transformed B lymphocytes. have. For gliomas, enhanced JNK / AP1 activity was observed in most primary brain tumor samples. In transformed B lymphocytes, BCL-ABL has been shown to activate the JNK pathway, upregulating the expression of the anti-apoptotic bc1-2 gene. Interestingly, multidrug resistance and hyperproliferation seen in refractory AML (acute myeloid leukemia) patients were causally linked to the sustained JNK activity present in the AML sample. Activation of JNK in leukemia cells resulted in the induced expression of efflux pumps such as mdr1 and MRP1 that contribute to multidrug resistance. In addition, genes that respond favorably to survival against oxidative stress, including glutathione-S-transferase π and γ-glutamyl cysteine synthase, have also been upregulated by an activated JNK pathway.

Kidney disease is characterized by a loss of nephron function caused by progressive glomerulosclerosis and tubulointerstitial fibrosis. Kidney disease can occur as a result of many symptoms, including inflammation, hypertension, diabetes or acute tissue damage caused by antibiotics, contrast agents or other nephrotoxic agents. JNK signaling has been shown to be upregulated in pathological samples from many human kidney diseases (1), including immune and non-immune mediated glomerulonephritis, diabetic nephropathy, hypertension, acute injury, and signaling in polycystic kidney disease (2). It seems to play a role. Strong evidence for the pivotal role of JNK and the therapeutic potential of JNK inhibitors is supported by studies in kidney injury animal models. JNK was increased in rat anti-glomerular basement membrane induced glomerulonephritis model, and renal function was improved by specific inhibitors in both acute and chronic disease legends (3). In addition, JNK was increased in models of renal ischemic-reperfusion injury (5,6) as well as in Dahl salt-sensitive hypertensive rats, ie hypertensive kidney disease (4) model. The cellular mechanisms by which JNK may contribute to kidney damage are, in part, the activation of pro-fibrotic and pro-apoptotic pathways directly in renal glomeruli and coronary epithelial (7) cells. As well as up-regulation of pro-inflammatory mediators in macrophages. The ability to improve kidney function by the inhibition of JNK in a complex disease model suggests JNK as an attractive target for the treatment of kidney disease of various etiologies.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I)

Where

m is 0 to 2;

n is 0 to 2;

p is 0 to 3;

X is CH or N;

R ¹ is each independently hydrogen or C _{1 - 6} alkyl, and;

R ² are each independently C _{1 - 6} alkyl, C _{1 - 6} alkoxy halo -C _{1 - 6} alkyl or halo -C _{1 - 6} alkoxy;

R ³ is C _{1 - 6} alkylsulfonyl -C _{1 - 6} alkyl, tetrahydro-thiophenyl-1,1-oxide, -C _{1 - 6} alkyl, or tetrahydro-thiopyran-1,1-oxide, -C _{1 - 6} alkyl ego;

R ⁴ are each independently C _{1 - 6} alkyl, C _{1 - 6} alkoxy halo -C _{1 - 6} alkyl or halo -C _{1 - 6} alkoxy;

R ⁵ is a group of formula a or b:

(A)

[Formula b]

q is 0 or 1;

r is 0 or 1;

Y is NR ⁹ or CR ¹⁰ R ¹¹ ;

R ⁶ and R ⁷ are each independently hydrogen, carboxy, carboxy -C _{1 - 6} alkyl ester or C _{1 - 6} alkyl; R ⁶ and R ⁷ together are C _{1 -} to form a ₂ alkylene;

R ⁸ is hydrogen or C _{1 - 6} alkyl, and;

R ⁹ is hydrogen or C _{1 - 6} alkyl, and;

R ¹⁰ is hydrogen or C _{1 - 6} alkyl, and;

R ¹¹ is hydrogen, C _{1 - 6 alkoxy, NH 2 C (O) -} , C 1 - 6 alkyl, hydroxy -C _{1 - 6} alkyl, carboxy, carboxy -C _{1 - 6} alkyl, carboxy -C _{1 - 6} alkyl ester or a carboxy -C _{1 - 6} alkyl, C _{1 - 6} alkyl ester.

The present invention also provides methods of making the compounds and methods of using the compounds for the treatment of JNK-mediated diseases and conditions.

All documents mentioned herein are incorporated herein by reference in their entirety.

Unless stated otherwise, the following terms used in this application, including the specification and claims, have the definitions given below. In the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, as used herein, the singular forms one or more subject matter, for example, a compound means one or more compounds or at least one compound. As such, the singular terms "at least one" and "at least one" may be used interchangeably herein.

As used herein (whether used in transition or claims), the terms "comprises" and "comprising" are to be interpreted to have an unrestricted meaning. That is, the term should be interpreted as a synonym for the phrase "having at least" or "including at least ". When used in the context of a method, the term "comprising" means that the method includes at least the steps mentioned, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the mentioned feature or component, but may include additional features or components.

Unless specifically stated otherwise, the word "or" as used herein is used in the "inclusive" sense of "and / or" and not in the "exclusive" sense of "either / or".

The term “independently” is used herein to indicate that the variable applies in any case, regardless of the presence or absence of the variable having the same or different definitions in the same compound. Thus, in compounds where R "appears twice and is defined as" independently carbon or nitrogen ", R" can both be carbon, R "can both be nitrogen, or one R" is carbon and the rest is nitrogen Can be.

Any variable (e.g. m, n, p, q, Q, r, R ¹ , R ² , R ³ , R ⁴ , X, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , Y ¹ , Y ² , Z ¹ and Z ² ) are present more than once in any moiety or formula depicting and describing a compound used or claimed in the present invention, their definitions in each case are different each time Is independent of their definition. In addition, combinations of substituents and / or variables are permissible only if such compounds produce stable compounds.

The symbol "*" at the end of the bond or "------" through the bond refers to the point of attachment to the rest of the molecule of the functional group or other chemical moiety that is each part of the molecule. Thus, for example, As follows:

Bonds shown in the ring system (as opposed to bonds linked at separate vertices) indicate that the bond can be attached to any suitable ring atom.

As used herein, the term "optionally" or "optionally" means that an event or situation described subsequently is not essential, but may occur, and that this description includes cases where an event or situation has occurred and where it has not occurred. it means. For example, "optionally substituted" means that the optionally substituted moiety may include hydrogen or a substituent.

The term " about "is used herein to mean approximately, near, roughly, or roughly. Where the term "about" is used in conjunction with a numerical range, it changes the range by extending the boundary above and below the quoted numerical range. In general, the term “about” is used herein to change numerical values above and below a recited value by an amount of change of 20%.

Certain compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers result from the movement of covalently bonded hydrogen atoms between two atoms. Tautomers are generally in equilibrium, and attempts to isolate individual tautomers typically produce mixtures whose chemical and physical properties are consistent with the mixture of compounds. The position of the equilibrium varies with the chemical characteristics in the molecule. For example, many aliphatic aldehydes and ketones, such as acetaldehyde, dominate the keto form whereas phenols dominate the enol form.

Technical and scientific terms used herein have the meanings that are commonly understood by one of ordinary skill in the art to which this invention belongs, unless defined otherwise. Reference is made herein to various methodologies and materials known to those skilled in the art. Note that the standard covers the general principles of pharmacology literature including the literature [Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10 th Ed., McGraw Hill Companies Inc., New York (2001)]. Any suitable material and / or method known to those skilled in the art can be used in the practice of the present invention. However, preferred materials and methods are described. Materials, reagents, and the like referenced in the following specification and examples are obtainable by commercial sources unless otherwise indicated.

The definitions described herein may be added to form chemically related combinations such as "heteroalkylaryl", "haloalkylheteroaryl", "arylalkylheterocyclyl", "alkylcarbonyl", "alkoxyalkyl", and the like. have. When the term "alkyl" is used as a suffix after another term, such as in "phenylalkyl" or "hydroxyalkyl", it is an alkyl as defined above which is substituted with one or two substituents selected from other specifically named groups. Refer to the group. Thus, for example, "phenylalkyl" refers to an alkyl group having one or two phenyl substituents and thus includes benzyl, phenylethyl and biphenyl. "Alkylaminoalkyl" is an alkyl group having one or two alkylamino substituents. "Hydroxyalkyl" means a straight or branched chain alkyl group having from 2 to 20 carbon atoms, such as 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) 3-hydroxypropyl, and the like. Accordingly, the term "hydroxyalkyl" as used herein is used to define a subset of heteroalkyl groups as defined below. The term-(ar) alkyl refers to an unsubstituted alkyl or aralkyl group. The term (hetero) aryl or (het) aryl refers to an aryl or heteroaryl group.

As used herein, the term “acyl” refers to a group of the formula —C (═O) R, wherein R is hydrogen or lower alkyl as described herein. As used herein, the term “alkylcarbonyl” refers to a group of formula C (═O) R, wherein R is alkyl as described herein. The term C _{1 -6-acyl} refers to a group of -C (= O) R containing 6 carbon atoms. As used herein, the term “arylcarbonyl” refers to a group of formula C (═O) R, wherein R is an aryl group; The term "benzoyl" as used herein refers to an "arylcarbonyl" group, where R is phenyl.

As used herein, the term "alkyl" refers to an unbranched or branched, saturated monovalent hydrocarbon residue containing 1 to 10 carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon residue containing from 1 to 6 carbon atoms. As used herein, "C _{1 -10} alkyl" refers to an alkyl composed of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to lower alkyl groups such as methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl Include.

When the term "alkyl" is used as a suffix after another term, such as in "phenylalkyl" or "hydroxyalkyl", it is an alkyl as defined above which is substituted with one or two substituents selected from other specifically named groups. It is intended to mean a group. Thus, for example, "phenylalkyl" refers to the radical R'R "-, where R 'is a phenyl radical and R" is an alkylene radical as described herein, wherein the point of attachment of said phenylalkyl moiety is It is understood to exist on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl and 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are similarly interpreted except that R 'is an aryl radical. The terms "(het) arylalkyl" or "(het) aralkyl" are interpreted analogously except that R 'is optionally an aryl or heteroaryl radical.

The term "alkylene" as used herein, unless otherwise specified, divalent saturated linear hydrocarbon radicals of 1 to 10 carbon atoms (eg, (CH ₂ ) _n ) or divalent saturated portions of 2 to 10 carbon atoms Topographic hydrocarbon radicals (eg, -CHMe- or -CH ₂ CH (i-Pr) CH _2- ). Except in the case of methylene, the open valence of the alkylene group is not attached to the same atom. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene and 2-ethylbutylene.

The term "alkenyl" means a linear monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms, such as ethenyl, propenyl, etc., containing one or more double bonds. do.

The term "alkoxy" as used herein refers to an -O-alkyl group, wherein alkyl is as defined above, for example methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy , i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, and isomers thereof. As used herein, "lower alkoxy" refers to an alkoxy group having a "lower alkyl" group as defined above. The "C _{1 -10} alkoxy" as used herein refers to an -O- alkyl, and wherein alkyl is C _{1 -10.}

As used herein, the term "alkylsulfonyl" refers to a group of -SO ₂ R, wherein R is alkyl as described herein.

As used herein, the term "alkylsulfonylalkyl" refers to a group of -R'SO ₂ R, wherein R is alkyl and R 'is alkylene as described herein. Examples of alkylsulfonylalkyl include 3-methanesulfonyl-propoxy 2-methanesulfonyl-ethoxy and the like.

As used herein, the term to "tetrahydro-thiophenyl-1,1-oxide, -C _{1 - 6} alkyl", and means a group, wherein R is alkylene as described herein, R 'is -RR-tetrahydro-thiophenyl Phenyl-1,1-oxide. Tetrahydro-thiophenyl 1,1-oxide, -C _{1 - 6} alkyl is for example 1,1-dioxo-tetrahydro--1λ ^{6-thiophen-3-ylmethyl} and 2- (1,1-dioxo- Tetrahydro-1λ ⁶ -thiophen-3-yl) -ethyl.

As used herein, the term "tetrahydro-thiopyran-1,1-oxide, -C _{1 - 6} alkyl", and means a group, wherein R is alkylene as described herein, R 'is tetrahydro-thio -RR Pyran-1,1-oxide. Tetrahydro-thiopyran-1,1-oxide, -C _{1 - 6} alkyl is for example 1,1-dioxo-hexahydro--1λ ^* 6 ^* - thiopyran-3-ylmethyl and 2- (1,1- Oxo-hexahydro-1λ ^* 6 ^* -thiopyran-3-yl) -ethyl.

The term "carboxy" as used herein, means a group of the formula -COOH.

As used herein, the term "carboxy alkyl ester" refers to a group of the formula -COOR, where R is alkyl as described herein.

The term "carboxy-alkyl" as used herein, means a group of the formula -R'-COOH, wherein R 'is alkylene as described herein.

As used herein, the term "carboxy-alkyl alkyl ester" refers to a group of the formula -R'-COOR, wherein R is alkyl and R 'is alkylene as described herein.

"Aryl" means a monovalent cyclic aromatic hydrocarbon residue consisting of a mono-, di-, or tricyclic aromatic ring. Aryl groups may be optionally substituted as described herein. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentarenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, Diphenylsulfyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperazinyl, benzo Piperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl and ethylenedioxyphenyl and the like, and partially hydrogenated derivatives thereof.

The term "base" includes, but is not limited to, NaOH, KOH, LiOH and alkali metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, cesium carbonate and the like.

"Cycloalkyl" or "carbocyclic ring" means a monovalent saturated carbocyclic moiety consisting of a mono- or bicyclic ring. Cycloalkyl may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkyl, unless specifically noted otherwise Amino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like, and partially unsaturated derivatives thereof.

"Heterocycloalkyl lower alkyl" means a moiety of the formula -R ^a -R ^b , wherein R ^a is lower alkylene and R ^b is heterocycloalkyl as described herein.

As used herein, the term “heteroaryl” or “heteroaromatic” contains 4 to 8 atoms per ring, including one or more N, O or S heteroatoms and the remaining ring atoms having one or more aromatic rings that are carbons, By monocyclic or bicyclic radical of 5 to 12 ring atoms, it is understood that the point of attachment of the heteroaryl radical is on the aromatic ring. As is known to those skilled in the art, heteroaryl rings have fewer aromatic features than all of their carbon counterparts. Thus, for the purposes of the present invention, heteroaryl groups need only have some aromatic features. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 or 6 ring atoms and 1 to 3 heteroatoms, including but not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, Imidazolyl, oxazole, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxolin, and these include hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, Alkylthio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarba Optionally substituted with one or more, preferably one or two substituents selected from moyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole. The bicyclic moiety may be optionally substituted in one of these rings, but the point of attachment is on a ring containing heteroatoms.

As used herein, the term “heterocyclyl”, “heterocycle” or “heterocycloalkyl” is 3 to 8 per ring comprising one or more ring heteroatoms (selected from N, O or S (O) _0-2 ). Monovalent saturated cyclic radicals consisting of one or more rings of two atoms, preferably one or two rings, which, unless stated otherwise, are optionally hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower halo Alkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsul To be independently substituted with one or more, preferably one or two substituents selected from fonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino There. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl , Morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.

As used herein, the term “hydroxyalkyl” refers to an alkyl radical described herein where one to three hydrogen atoms on different carbon atoms are replaced with hydroxyl groups.

Commonly used abbreviations are: acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), atmosphere (Atm), 9-borabicyclo [3.3.1] nonane (9-BBN or BBN) , t-butoxycarbonyl (Boc), di-t-butyl pyrocarbonate or boc anhydride (BOC ₂ O), benzyl (Bn), butyl (Bu), chemical abstract registration number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo [2.2.2] octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba ), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N'- Dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD) , Di-iso-butylaluminum hydride (DIBAL or DIBAL-H), Di-iso-propylethylamine (DIPEA), N, N-dimethyl acetamide (DMA), 4-N, N-dimethylaminopyridine (DMAP), N, N-dimethylformamide (DMF), di Methyl sulfoxide (DMSO), 1,1'-bis- (diphenylphosphino) ethane (dppe), 1,1'-bis- (diphenylphosphino) ferrocene (dppf), 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acid ethyl ester (EEDQ), Diethyl ether (Et ₂ O), O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc) , 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), iso-propanol (IPA), lithium hexamethyl disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO _2- (mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA) ), Mass spectrum (ms), methyl t-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxylic anhydride (NCA), N-chlorosuccinimide (NCS), N-methyl Morpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr) , Pounds per square inch (psi), pyridine (pyr), room temperature (rt or RT), t-butyldimethylsilyl or t-BuMe ₂ Si (TBDMS), triethylamine (TEA or Et ₃ N), 2,2 , 6,6-tetramethylpiperidine 1-oxyl (TEMPO), triplate or CF ₃ SO _2- (Tf), trifluoroacetic acid (TFA), 1,1'-bis-2,2,6, 6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography Photography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me ₃ Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C ₆ H ₄ SO ₂ Or tosyl (Ts), N-urethane-N-carboxylic anhydride (UNCA). Conventional nomenclature, including the prefix normal (n-), iso (i-), secondary (s-), tertiary (t-) and neo has common meaning when used with alkyl moieties (J [J] Rigaudy and DP Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford].

 "Heteroaryl" means a monocyclic or bicyclic moiety of 5 to 12 ring atoms containing one, two or three heteroatoms selected from N, O and S and the remaining ring atoms having at least one aromatic ring which is C Where the point of attachment of the heteroaryl radical is understood to be on the aromatic ring. Heteroaryl rings may be optionally substituted as described herein. Examples of heteroaryl residues include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, thiophenyl, fura Neil, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuryl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl , Benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindoleyl, indazolyl, triazolyl, triazinyl, quinoxalinyl, furinyl, quinazolyl Nil, quinolizinyl, naphthyridinyl, putridinyl, carbazolyl, azepinyl, diazefinyl and acridinyl, and the like, and partially hydrogenated derivatives thereof.

The terms "halo", "halogen" and "halide" are used interchangeably herein and refer to fluorine, chlorine, bromine and iodine.

"Haloalkyl" means alkyl as described herein in which one or more hydrogens are replaced with the same or different halogens. The term "lower haloalkyl" denotes a straight or branched chain hydrocarbon moiety containing 1 to 6 carbon atoms substituted with one or more halogen atoms. Examples of haloalkyl include -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CCl ₃ , -CF ₂ CF ₃ , -CF ₃ , and the like.

"Heterocyclyl" or "heterocycloalkyl" means a monovalent saturated moiety consisting of one or two rings incorporating one, two, three or four heteroatoms (selected from nitrogen, oxygen and sulfur). Heterocyclyl rings may be optionally substituted as described herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, Pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl , Thiadiazolidinyl, benzothiazolidinyl, benzoazolidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamopolynyl, thiamopolyylsulfoxide, thiamopolyyl Sulfones, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.

Preferred radicals for the chemical groups defined above are those specifically exemplified in the examples.

"Optionally substituted" means a substituent independently substituted with 0 to 3 substituents selected from lower alkyl, halo, OH, cyano, amino, nitro, lower alkoxy and halo-lower alkyl.

Preferred “oxidizing agents” include peracids such as phosphorus-chloroperbenzoic acid (MCPBA) and peracetic acid, but other oxidizing agents such as hydrogen peroxide, permanganate salt or persulfate salt may be used to oxidize the thioether to sulfone. Can be.

"Leaving group" typically means a group having a meaning associated with it in synthetic organic chemistry, i.e., an atom or group replaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy and thienyloxy, dihalophos Pinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy and the like.

“Arbitrarily” or “arbitrarily” means that an event or situation described subsequently may not need to occur, and the description includes when an event or situation occurs and when it does not occur.

"Agonist" refers to a compound that enhances the activity of another compound or receptor site.

An “antagonist” refers to a compound that reduces or inhibits the action of another compound or receptor site.

The term “drug candidate” refers to a compound or agent intended to test for possible effects on the treatment of a disease state in an animal, regardless of whether the drug candidate has any known biological activity.

As used herein, the term “homologous” functions substantially the same in different subject species to the extent that it is recognized in the art to be different versions of the same protein, which is essentially different in sequence sequence from that in which the identified species. It means a protein sharing. Thus, for example, human ERG, mouse ERG and rat ERG are all considered to be homologous to each other.

"Modulator" means a molecule that interacts with a target. Interactions include, but are not limited to, agents, antagonists, and the like described herein.

 "Disease" and "disease state" mean any disease, condition, symptom, disorder or sign.

The term "cell line" refers to a clone of endless growth mammalian cells. A "stable" cell line is a cell line that exhibits substantially constant characteristics over time (eg, double proliferation each). Stable cell lines within the scope of the present invention can provide a seal resistance of greater than about 50 MOhm, a current amplitude of greater than about 200 pA, and a current that does not vary by greater than about 20% over 1 hour under controlled conditions. Provide a substantial cell fraction that can provide amplitude.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound as described herein. The salts include:

(1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid Acid addition salts formed with maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid and trimethylacetic acid; or

(2) Salts formed when acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions or aluminum ions, or coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein for the same acid addition salt.

Preferred pharmaceutically acceptable salts are salts formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium.

"Solvate" means a solvent addition form containing a stoichiometric or non stoichiometric amount of solvent. Some compounds have a tendency to capture fixed molecule ratios of solvent molecules in the crystalline solid state, thus forming solvates. The solvate formed is a hydrate when the solvent is water, and the solvate formed is an alcoholate when the solvent is alcohol. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water maintains its molecular state as H ₂ O, which combination may form one or more hydrates.

"Subject" includes mammals and birds. "Mammal" means any member of a mammalian class, including but not limited to human; Non-human primates such as chimpanzees and other apes and monkey species; Domestic animals such as cattle, horses, sheep, goats, and swine; Pets such as rabbits, dogs and cats; Rodents such as rats, mice and laboratory animals including guinea pigs and the like. The term "subject" does not mean a particular age or gender.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect the treatment for the disease state. A "therapeutically effective amount" will vary depending on the compound, the disease state to be treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the medical or veterinary physician, and other factors.

As used herein, “pharmacological effect” includes effects produced in a subject that achieves the intended therapeutic purpose. For example, the pharmacological effect would be to provide prevention, alleviation or reduction of urinary incontinence in the treated subject.

"Disease state" means any disease, condition, symptom or sign.

 "Treating" or "treatment" of a disease state includes:

(i) preventing a disease state, ie, in a subject who may be exposed to or susceptible to a disease state but has not yet exhibited or experienced symptoms of the disease state, such that the clinical symptoms of the disease state do not develop;

(ii) inhibiting the disease state, ie, inhibiting the development of the disease state or clinical symptoms thereof; or

(iii) alleviating the disease state, ie, inducing a temporary or permanent weakening of the disease state or its clinical symptoms.

All patents and documents described herein are hereby incorporated by reference in their entirety.

Nomenclature and structure

In general, the nomenclature used herein is based on the AUTONOM (tradename) version 4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. The chemical structures shown herein are prepared using ISIS® version 2.2. Any open valence representing a carbon, oxygen, sulfur or nitrogen atom in the structure herein refers to the presence of a hydrogen atom unless otherwise specified. When a nitrogen-containing heteroaryl ring is represented by an open valence on a nitrogen atom, a variable such as R ^a , R ^b or R ^c appears on the heteroaryl ring, which variable may be bound to or together with the open valence nitrogen. If a chiral center is present in the structure, but no specific stereochemistry appears for the chiral center, all enantiomers associated with the chiral center are encompassed by the structure. Where the structures shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms shown in the structures herein are intended to encompass all natural isotopes of these atoms. Thus, for example, hydrogen atoms represented herein mean deuterium and tritium, and carbon atoms mean C ¹³ and C ¹⁴ isotopes.

In certain embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided:

Formula I

Where

m is 0 to 2;

n is 0 to 2;

p is 0 to 3;

X is CH or N;

R ¹ is each independently hydrogen or C _{1 - 6} alkyl, and;

R ² are each independently C _{1 - 6} alkyl, C _{1 - 6} alkoxy halo -C _{1 - 6} alkyl or halo -C _{1 - 6} alkoxy;

R ³ is C _{1 - 6} alkylsulfonyl -C _{1 - 6} alkyl, thiophenyl-1,1-oxide, -C _{1 - 6} alkyl, or tetrahydro-thiopyran-1,1-oxide, -C _{1 - 6} alkyl;

R ⁴ are each independently C _{1 - 6} alkyl, C _{1 - 6} alkoxy halo -C _{1 - 6} alkyl or halo -C _{1 - 6} alkoxy;

R ⁵ is a group of formula a or b:

A

Formula b

q is 0 or 1;

r is 0 or 1;

Y is NR ⁹ or CR ¹⁰ R ¹¹ ;

R ⁶ and R ⁷ are each independently hydrogen or C _{1 - 6} alkyl; R ⁶ and R ⁷ together are C _{1 -} to form a ₂ alkylene;

R ⁸ is hydrogen or C _{1 - 6} alkyl, and;

R ⁹ is hydrogen or C _{1 - 6} alkyl, and;

R ¹⁰ is hydrogen or C _{1 - 6} alkyl, and;

R ¹¹ is C _{1 - 6} alkyl, hydroxy -C _{1 - 6} alkyl, carboxy, carboxy -C _{1 - 6} alkyl, carboxy -C _{1 - 6} alkyl ester or carboxy -C _{1 - 6} alkyl, C _{1 - 6} alkyl ester to be.

In certain embodiments of formula I, m is 0 or 1.

In certain embodiments of formula I, m is 0.

In certain embodiments of formula I, m is 1.

In certain embodiments of formula I, n is 0 or 1.

In certain embodiments of formula I, n is 0.

In certain embodiments of formula I, n is 1.

In certain embodiments of formula I, p is 0-2.

In certain embodiments of formula I, p is 0 or 1.

In certain embodiments of formula I, p is 0.

In certain embodiments of formula I, p is 1.

In certain embodiments of formula I, q is 0.

In certain embodiments of formula I, q is 1.

In certain embodiments of formula I, r is 0.

In certain embodiments of formula I, r is 1.

In certain embodiments of formula I, X is CH.

In certain embodiments of formula I, X is N.

In certain embodiments of formula I, R < ¹ > is hydrogen.

In certain embodiments of formula I, R ¹ is C _{1 - 6} is alkyl.

In certain embodiments of formula I, R ² are each independently C _{1 - 6} alkoxy, or a _{halo-6-alkyl,} C _1.

In certain embodiments of formula I, R ² are each independently C _{1 - 6} alkyl or a halo.

In certain embodiments of formula I, R ² is C _{1 - 6} is alkyl.

In certain embodiments of formula I, R ³ is C _{1 - 6} alkyl, a _{- 6} alkylsulfonyl -C _1.

In certain embodiments of formula I, R ³ is tetrahydro-thiophenyl-1,1-oxide, -C _{1 - 6} alkyl is.

In certain embodiments of formula I, R ³ is tetrahydro-thiopyran-1,1-oxide, _- C ₁ - ₆ is alkyl.

In certain embodiments of formula I, R ³ is 3-methanesulfonyl-propyl or 1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethyl.

In certain embodiments of formula I, R ³ is 3-methanesulfonyl-propyl.

In certain embodiments of formula I, R ³ is 1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethyl.

In certain embodiments of formula I, R ⁴ are each independently C _{1 - 6} alkyl or a halo.

In certain embodiments of formula I, R ⁴ is C _{1 - 6} is alkyl.

In certain embodiments of formula I, R ⁵ is a group of formula a.

In certain embodiments of formula I, R ⁵ is a group of formula b.

In certain embodiments of formula I, R ⁶ and R ⁷ are each independently hydrogen or C _{1 - 6} alkyl; R ⁶ and R ⁷ together are C _{1 -} to form a ₂ alkylene.

In certain embodiments of formula I, R ⁶ is hydrogen, carboxy, carboxy -C _{1 - 6} alkyl ester is.

In certain embodiments of formula I, R ⁶ is hydrogen.

In certain embodiments of formula I, R ⁶ is C _{1 - 6} is alkyl.

In certain embodiments of formula I, R ⁷ is hydrogen or methyl.

In certain embodiments of formula I, R ⁷ is hydrogen.

In certain embodiments of formula I, R ⁷ is C _{1 - 6} is alkyl.

In certain embodiments of formula I, R ⁶ and R ⁷ together are C _{1 -} to form a ₂ alkylene.

In certain embodiments of formula I, R ⁶ and R ⁷ together form methylene.

In certain embodiments of formula I, R ⁶ and R ⁷ together form ethylene.

In certain embodiments of formula I, R ⁸ is hydrogen.

In certain embodiments of formula I, R ⁸ is C _{1 - 6} is alkyl.

In certain embodiments of formula I, Y is NR ⁹ .

In certain embodiments of formula I, Y is CR ¹⁰ R ¹¹ .

In certain embodiments of formula I, R < ⁹ > is hydrogen.

In certain embodiments of formula I, R ⁹ is C _{1 - 6} is alkyl.

In certain embodiments of formula I, R < ¹⁰ > is hydrogen.

In certain embodiments of formula I, R ¹⁰ is C _{1 - 6} is alkyl.

In certain embodiments of formula I, R ¹¹ is C _{1 - 6} alkyl, hydroxy -C _{1 - 6} alkyl, carboxy, carboxy -C _{1 - 6} alkyl, carboxy -C _{1 - 6} -C ₁ alkyl ester or _carboxy-6 alkyl C _{1 - 6} alkyl ester.

In certain embodiments of formula I, R ¹¹ is C _{1 - 6} alkyl, a _{- 6} alkyl, hydroxy -C _1.

In certain embodiments of formula I, R ¹¹ is C _{1 - 6} is alkyl.

In certain embodiments of formula I, R ¹¹ is hydroxy -C _{1 - 6} alkyl is.

In certain embodiments of formula I, R ¹¹ is carboxy.

In certain embodiments of formula I, R ¹¹ is a carboxy-C _{1 - 6} alkyl ester.

In certain embodiments of formula I, R ¹¹ is a carboxy -C _{1 - 6} alkyl is.

In certain embodiments of formula I, R ¹¹ is a carboxy -C _{1 - 6} alkyl, -C _{1 - 6} alkyl ester.

Representative compounds encompassed by the present invention and within the scope of the present invention are provided in Table 1 below with the melting point and IC ₅₀ affinity values of the selected compounds.

Way

In one aspect, the present disclosure provides a method of treating a JNK-mediated disorder in a subject having a JNK-mediated disorder comprising administering to the subject in need thereof any therapeutically effective amount of the compound.

In certain embodiments of the methods of treating JNK-mediated disorders, JNK-mediated disorders are characterized by cell proliferation.

In certain embodiments of the methods of treating JNK-mediated disorders, the JNK-mediated disorder is arthritis.

In certain embodiments of the method of treating JNK-mediated disorders, arthritis is rheumatoid arthritis.

In certain embodiments of the methods of treating JNK-mediated disorders, the JNK-mediated disorder is asthma.

In certain embodiments of the method of treating JNK-mediated disorders, the JNK-mediated disorder is diabetes.

In certain embodiments of the methods of treating JNK-mediated disorders, the JNK-mediated disorder is Alzheimer's disease.

In certain embodiments of the methods of treating JNK-mediated disorders, the JNK-mediated disorder is Parkinson's disease.

In certain embodiments of the methods of treating JNK-mediated disorders, the JNK-mediated disorder is ischemic stroke.

In certain embodiments of the methods of treating JNK-mediated disorders, the JNK-mediated disorder is cancer.

In certain embodiments of the method of treating JNK-mediated disorders, the JNK-mediated disorder is brain cancer.

In certain embodiments of the methods of treating JNK-mediated disorders, the JNK-mediated disorder is leukemia.

In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of any one of the preceding embodiments, mixed with one or more pharmaceutically acceptable carriers, excipients or diluents.

In a further aspect, the present application provides any use of said compound for the manufacture of a medicament for the treatment and / or prophylaxis of JNK-mediated disorder treatment.

In certain embodiments of the use of the compounds for the manufacture of a medicament, the JNK-mediated disorder is an autoimmune disorder, an inflammatory disorder, a metabolic disorder, a neurological disease or a cancer.

In certain embodiments of the use of the compounds for the manufacture of a medicament, the JNK-mediated disorder is rheumatoid arthritis, asthma, type 2 diabetes, Alzheimer's disease, Parkinson's disease or stroke.

In a further aspect, the present disclosure provides a compound of any of the above embodiments for use in the treatment of a JNK-mediated disorder.

The compounds of the present invention are JNK modulators and are therefore expected to be effective in treating a wide range of JNK-mediated disorders. Examples of JNK-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, metabolic disorders, neurological diseases and cancer. Thus, the compounds of the present invention can be used to treat one or more of these disorders. In some embodiments, the compounds of the present invention can be used to treat JNK-mediated disorders such as rheumatoid arthritis, asthma, type 2 diabetes, Alzheimer's disease, Parkinson's disease or stroke.

Administration and pharmaceutical composition

The present invention relates to one or more pharmaceutically acceptable carriers, together with one or more compounds of the present invention, or individual isomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof, and optionally Pharmaceutical compositions comprising other therapeutic and / or prophylactic ingredients.

In general, the compounds of the present invention may be administered in therapeutically effective amounts by any acceptable mode of administration for agents that provide similar utility. Suitable dosage ranges depend on a number of factors, such as the severity of the disease to be treated, the age and relative health of the subject, the efficacy of the compound used, the route and form of administration, the indications that are targeted for administration, and the choice and experience of the attending physician, Typically it is 1 to 500 mg per day, preferably 1 to 100 mg per day, most preferably 1 to 30 mg per day. One skilled in the art of treating such a disease will be able to determine the therapeutically effective amount of a compound of the invention for a given disease without undue experimentation and according to personal knowledge and the disclosure of the present application.

Compounds of the invention are pharmaceutical formulations comprising those suitable for oral (including oral and sublingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intradural, subcutaneous and intravenous) administration Or in a form suitable for administration by inhalation or aeration. The preferred mode of administration is generally oral, using a convenient daily dosage plan that can be adjusted according to the degree of pain.

The compounds of the present invention may take pharmaceutical compositions and unit dosage forms in combination with one or more conventional adjuvants, carriers or diluents. The pharmaceutical compositions and unit dosage forms may consist of conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, wherein the unit dosage form is any equivalent to the daily dosage range to be used. It may contain a suitable effective amount of the active ingredient. Pharmaceutical compositions can be used orally as solids (eg, tablets or filled capsules, semisolids, powders, sustained release formulations), or liquids (eg, solutions, suspensions, emulsions, elixirs or filled capsules); Or in the form of suppositories for rectal or vaginal administration; Or for parenteral use, in the form of sterile injectable solutions.

Accordingly, formulations containing about 1 mg, or more broadly about 0.01 to about 100 mg of active ingredient per tablet are suitable representative unit dosage forms.

The compounds of the present invention can be formulated in a variety of oral dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound of the invention or a pharmaceutically acceptable salt thereof as the active ingredient. Pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more substances which may act as diluents, flavoring agents, solubilizing agents, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. In powders, the carrier is a finely divided solid which is generally a mixture with the finely divided active component. In tablets, the active ingredient is mixed with the carrier generally having the necessary binding capacity in suitable proportions and compacted to the desired shape and size. Powders and tablets preferably contain about 1 to about 70% of active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter and the like. do. The term “formulation” is intended to include formulations of the active compounds with encapsulating material as carriers, with or without a carrier, providing a capsule in which the active ingredient is surrounded by a carrier associated with it. Similarly, sachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. Emulsions may be prepared in solution, for example in aqueous propylene glycol, or may contain emulsifiers such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

Compounds of the invention may be formulated for parenteral administration (eg, injection, eg, bolus injection or continuous infusion), and may be in unit dosage forms of ampoules, pre-filled syringes, small volume infusions, or It may be provided in a multi-dose container with added preservatives. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, for example a solution in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil) and injectable organic esters (eg ethyl oleate), which may be formulated such as preservatives , Wetting agents, emulsifying or suspending agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by lyophilization from solution or aseptic isolation of sterile solid, which is composed with a suitable vehicle, eg sterile water, free of pyrogen before use.

The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as transdermal patches. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents. Formulations suitable for topical administration in the oral cavity include lozenges comprising the active agent in a frankincense base, typically sucrose and acacia or tragacanth; Perfumes containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; And mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a mold of convenient size, cooled and solidified.

The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers in addition to the active ingredient are known in the art as suitable.

The compounds of the present invention may be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional methods, for example using a dropper, pipette or spray. The formulations may be presented in a single dose or in multiple dosage forms. In the latter case a dropper or pipette can be achieved by having the patient administer a suitable predetermined volume of solution or suspension. In the case of atomization, it can be achieved, for example, by means of a metering atomization atomizing pump.

The compounds of the present invention may be formulated for administration to aerosols, especially for administration to airways, including intranasal administration. The compound will generally have a small particle size, for example a size of about 5 μm or less. The particle size can be obtained by methods known in the art, for example by micronization. The active ingredient may be pressurized using a suitable propellant such as chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Is provided. Aerosols may also conveniently contain surfactants such as lecithin. The dose of the drug can be controlled by the metering valve. Alternatively, the active ingredient may be provided in the form of a powder mixture of the compound in a dry powder, for example a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). Can be. The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example as a cartridge or capsule of a gelatin or blister pack, wherein the powder may be administered by an inhaler.

If desired, the formulations may be prepared with an enteric coating suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated into transdermal or subcutaneous drug delivery devices. Such delivery systems are advantageous when sustained release of the compound is required and patient compliance with the treatment regimen is important. Compounds within the transdermal delivery system are often attached to a solid support for skin adhesion. Compounds of interest can also be combined with penetration enhancers such as azone (1-dodecylazacycloheptan-2-one). The sustained delivery system is inserted into the subdermal layer via subcutaneous surgery or injection. Subcutaneous implantation encapsulates the compound in lipid soluble membranes such as silicone rubber, or biodegradable polymers such as polylactic acid.

The pharmaceutical preparations are preferably unit dosage forms. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a package preparation, wherein the package contains discrete amounts of preparations such as packet tablets, capsules and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, sachet or lozenge itself, or may be in the form of any suitable number of packages.

Other suitable pharmaceutical carriers and formulations thereof are described in Remington: The Science and Practice Pharmacy 1995, edited by E.W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing the compounds of the present invention are described below.

Additional objects, advantages and novel features of the present invention will become apparent to those skilled in the art upon consideration of the following examples, but such examples are not intended to limit the present invention.

synthesis

Compounds of the invention can be prepared by a variety of methods shown below and illustrated in the exemplary synthetic schemes shown below.

Starting materials and reagents used in the preparation of these compounds are generally available from commercial sources such as Aldrich Chemical Co., or may be found in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991 , Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; And according to the procedures described in Organic Reactions, Wiley & Sons: New York, 1991 , Volumes 1-40, by methods known to those skilled in the art. The following synthetic schemes merely illustrate some of the ways in which the compounds of the present invention can be synthesized, and various modifications to the synthetic schemes can be made and will be suggested to those skilled in the art in accordance with the disclosure herein.

Starting materials and intermediates of the synthesis scheme can be isolated and purified as needed using conventional techniques such as, but not limited to, filtration, distillation, crystallization and chromatography. Such materials can be characterized using conventional means, such as physical constants and spectral data.

Unless stated to the contrary, the reactions described herein are from about −78 ° C. to about 150 ° C., more preferably from about 0 ° C. to about 125 ° C., most preferably and conveniently at room temperature (or ambient temperature), such as about 20 ° C. Is carried out under an inert atmosphere in a reaction mixture in the reaction temperature range of.

Scheme A below illustrates one synthetic process that may be used to prepare certain compounds of Formula I, wherein R is lower alkyl and may be the same or different when each occurs, m, n, p, q, r , X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined herein.

[Reaction Scheme A]

In step 1 of Scheme A, an hydroxyindole compound (a) is reacted with a halide compound (b) to perform an O-alkylation reaction to obtain an indole compound (c). The reaction can be carried out, for example, in the presence of potassium carbonate and potassium iodide in a polar aprotic solvent such as acetonitrile.

In step 2, indole (c) is reacted with dichloropyrimidine (d) to give indole pyrimidine compound (e). The reaction of step 2 may be carried out in the presence of HOBt and potassium carbonate under polar solvent conditions.

In step 3, compound (e) is reacted with cyclohexylamine (f) to give indole pyrimidine amine compound (g). The reaction of step 3 can be carried out in the presence of potassium carbonate under polar solvent conditions.

In step 4, the carboxylate group of compound g is hydrolyzed to yield the corresponding carboxylic acid compound h. Hydrolysis in this step can be achieved, for example, in the presence of a base such as sodium hydroxide and under polar protic solvent conditions.

In step 5, amide formation in which compound h reacts with amine i is carried out to afford amide compound j which is a compound of formula I according to the invention. Amide formation can be carried out via acid chloride intermediates (not shown) or using various amide coupling agents such as ECDI or other carbodiimides.

Various modifications may be possible in the course of Scheme A and will suggest itself to those skilled in the art. Specific details for producing compounds of the invention are described in the Examples below.

The following abbreviations can be used in the following Preparations and Examples.

Abbreviation

Ac ₂ O acetic anhydride

AcOH acetic acid

BOP Benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate

DBU 1,8-Diazabicyclo [5.4.0] undec-7-ene

DCE 1,2-dichloroethane

DCM dichloromethane / methylene chloride

DIPEA diisopropylethylamine

DMA dimethyl acetamide

DMF N, N-dimethylformamide

DMSO dimethylsulfoxide

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

Et ₂ O diethyl ether

EtOH Ethanol / Ethyl Alcohol

EtOAc ethyl acetate

HOBt 1-hydroxybenzotriazole

LDA Lithium Diisopropylamide

LiHMDS lithium bis (trimethylsilyl) amide

m-CPBA 3-chloroperoxybenzoic acid

MeOH Methanol / Methyl Alcohol

MW microwave

NMP 1-methyl-2-pyrrolidinone

PMB 4-methoxy benzyl

PyBOP Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

RT room temperature

TBME t-butyl methyl ether

TFA Trifluoroacetic acid

Tf ₂ O trifluoromethanesulfonic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

Example

The following preparations and examples are presented to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be regarded as limiting the scope of the invention, they should only be regarded as exemplary and representative of the invention.

Example  1: (1,1- Dioxo - Tetrahydro -1λ ^* 6 ^* -Thiophen-3-yl) -methanol

LAH (35 mL of 1 M THF solution) was added dropwise to a solution of 1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophene-3-carboxylic acid (5.0 g) in THF (100 mL). The mixture was stirred at rt for 5 h and then cooled in an ice bath. Water (3 mL) and NaOH (6 mL of 15% aqueous solution) were added and the mixture was stirred at rt for 60 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3.59 g of (1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophen-3-yl) -methanol.

Example  2: toluene-4- Sulfonic acid  1,1- Dioxo - Tetrahydro -1λ ^* 6 ^* -Thiophen-3-ylmethyl ester

(1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophen-3-yl) -methanol (3.59 g), 4-toluenesulfonyl chloride (9.11 g) and pyridine (5.8 in chloroform (50 mL) mL) was heated to 60 ° C. and stirred overnight. The reaction mixture was cooled down, diluted with HCl (100 mL, 1 N) and extracted with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexanes) to give 4.012 g of toluene-4-sulfonic acid 1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophen-3-ylmethyl ester .

Example  3: 4- (3- Methylsulfanyl - Propoxy ) -1- (2- Methylsulfanyl -Pyrimidin-4-yl) -1H-indole

4- (3-methylsulfanyl-propoxy) -1H-indole (400.88 g) in THF (250 mL), K ^t BuO (2 L, 1 N) and 4-chloro-2- in THF (350 mL) Methylsulfanyl-pyrimidine (381 g) was combined while cooling to maintain temperature under 40 ° C. and stirred at room temperature for 1 hour. The solvent is then removed in vacuo, the solid is suspended in MeOH, filtered, washed with MeOH and water and dried to provide 87.56% of 4- (3-methylsulfanyl-propoxy) -1- (2-methylsulpa Neyl-pyrimidin-4-yl) -1H-indole was obtained.

Example  4: 1- (2- Methanesulfinyl -Pyrimidin-4-yl) -4- (3- Methanesulfonyl - Propoxy ) -1H-indole

MCPBA (204.3 g, 77%) in DCM (310 mL) and MeOH (155 mL) was added 4- (3-methylsulfanyl-propoxy) -1- (2 in DCM (590 mL) and methanol (145 ml). -Methylsulfanyl-pyrimidin-4-yl) -1H-indole (100.0 g) was added dropwise at -5 ° C for 1.5 hours. Further MCPBA (12.0 g) was added at 2 ° C. and after 20 minutes, the reaction mixture was diluted with slowly adding MTBE (900 mL) at 12 ° C. for 20 minutes. The mixture was stirred at 20-22 ° C. for 1.5 h. MTBE (300 mL) was then added, the mixture was filtered for 20 minutes, then the solids were rinsed with MTBE (2 × 200 mL) and the solvent removed in vacuo to give 1- (2-methanesulfinyl-pyrimidine- 4-yl) -4- (3-methanesulfonyl-propoxy) -1H-indole (90.2%) was obtained.

Example  5: 4- {4- [4- (3- Methanesulfonyl - Propoxy ) -Indol-1-yl] -pyrimidin-2- Amino } - Cyclohexanecarboxylic acid methyl  Ester

4-Amino-cyclohexanecarboxylic acid ethyl ester (550 g) and DIPEA (815 mL) were added 1- (2-methanesulfinyl-pyrimidin-4-yl) -4- (3-methanesulfur in DMA (2.5 L). Ponyl-propoxy) -1H-indole (746.7 g) was added and the mixture was heated to 120 ° C. for 4 hours and then cooled to room temperature. Water (3 L) was added dropwise, the resulting precipitate was collected by filtration, washed with H ₂ O and MeOH, dried in vacuo at 48 ° C. overnight to afford 4- {4- [4- (3-methanesulfonyl-pro Foxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid methyl ester (90%) was obtained.

Example  6: 4- (3- Methanesulfonyl - Propoxy ) -1H-indole

1-chloro-3- (methanesulfonyl) -propane (160 g) is added to 1H-indol-4-ol (108.77 g) in MeCN (1 L), and K ₂ CO ₃ (338 g) and KI ( 13.36 g) was added. The reaction mixture was stirred overnight at 80 ° C., then cooled and filtered through celite. The filtrate was vacuum distilled and the solvent replaced with DCM (700 mL). The mixture was filtered, the solvent removed in vacuo and replaced with MeOH (600 mL). The solvent was partially removed in vacuo at 40 ° C. and crystallization occurred. After cooling, additional MeOH was added and the slurry was filtered. The collected solids were rinsed with cold MeOH and dried overnight in vacuo at 35 ° C. under N ₂ to afford 4- (3-methanesulfonyl-propoxy) -1H-indole (82%).

Example  7: 1- (2- Chloro -Pyrimidin-4-yl) -4- (3- Methanesulfonyl - Propoxy ) -1H-indole

4- (3-methanesulfonyl-propoxy) -1H-indole (188.1 g), 2,4-dichloropyrimidine (221.25 g), HOBT (20.08 g), K ₂ CO ₃ (143.68 g) and DMA (1.6 L) was heated to 85 ° C. for 20 hours. Then IPA (5 L) was added and the mixture was stirred for 20 minutes, then cooled to 0 ° C. for 3 hours and filtered. The collected solids were rinsed with IPA and water and the solids were dried in vacuo at 55 ° C. for 4 days to afford 1- (2-chloro-pyrimidin-4-yl) -4- (3-methanesulfonyl-propoxy) -1H -Indole (94%) was obtained.

Example  8: (2- Propylsulfanyl -Pyrimidin-4-yl)- Hydrazine

4-Chloro-2-propylsulfanyl-pyrimidine (15.03 g), hydrazine (10.69 g) and potassium carbonate (15.37 g) were added to ethanol (150 mL) and the mixture was heated to 80 ° C for 3 hours. The mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed (CH ₂ Cl ₂ / hexanes via silica) to afford 7.036 g of (2-propylsulfanyl-pyrimidin-4-yl) -hydrazine.

Example  9: 4- Methoxy -1- (2- Propylsulfanyl -Pyrimidin-4-yl) -1H- Indazole

(2-propylsulfanyl-pyrimidin-4-yl) -hydrazine (7.036 g), 2-fluoro-6-methoxy-4-propylsulfanyl-benzaldehyde (5.524 g) and DB (16.373 g) Was added to DMSO (70 mL) and the mixture was stirred at room temperature for 1 hour and then at 80 ° C. for 1 hour. The mixture was cooled down, diluted with water and filtered. The collected solid was washed with water and dried under reduced pressure to afford 4-methoxy-1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole.

Example  10: 1- (2- Propylsulfanyl -Pyrimidin-4-yl) -1H- Indazole -4-ol

4-methoxy-1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole was dissolved in methylene chloride (100 mL) and the mixture was cooled to -78 ° C and stirred. BBR ₃ (152.62 μL) was added and the mixture was stirred at rt overnight. The mixture was partitioned between water and methylene chloride and the combined organic layers were washed with water, saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give 1- (2-propylsulfanyl- Pyrimidin-4-yl) -1H-indazol-4-ol was obtained.

Example  11: 4- (2- Methylsulfanyl - Ethoxy ) -1- (2- Propylsulfanyl -Pyrimidin-4-yl) -1H-indazole

1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazol-4-ol (600 mg), potassium carbonate (1.104 g) and 1-chloro-2-methylsulfanyl-ethane (401.9 mg) was added to NMP (6 mL) and the mixture was heated to 80 ° C. for 3 hours. The mixture was cooled down, diluted with water and filtered. The collected solids were washed with water and dried under reduced pressure to afford 705 mg of 4- (2-methylsulfanyl-ethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indazole. Obtained.

Example  12: 4- (2- Methanesulfonyl - Ethoxy ) -1- [2- (propane-1- Sulfonate ) -Pyrimidin-4-yl] -1H- Indazole

4- (2-Methylsulfanyl-ethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1 H-indazole (705 mg) and meta-perchlorobenzoic acid (2.109 g, 77% Solid) was added to methylene chloride (10 mL) and the mixture was stirred at rt overnight. The reaction mixture was quenched by addition of aqueous sodium bisulfite (10%) and extracted with methylene chloride. The combined organic layers were washed with water, saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford 4- (2-methanesulfonyl-ethoxy) -1- [2- (propane -1-sulfonyl) -pyrimidin-4-yl] -1 H-indazole.

Example  13: 4- {4- [4- (2- Methanesulfonyl - Ethoxy ) - Indazole -1-yl] -pyrimidin-2- Amino } - Cyclohexanecarboxylic acid  Ethyl ester

In general, 4-amino-cyclohexanecarboxylic acid ethyl ester was prepared according to the procedure of Example 5 to 4- (2-methanesulfonyl-ethoxy) -1- [2- (propane-1-sulfonyl) -pyrimidine-4 4- {4- [4- (2-methanesulfonyl-ethoxy) -indazol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid by reaction with -yl] -1H-indazole Ethyl ester was prepared.

Example  14: 4- {4- [4- (3- Methanesulfonyl - Propoxy ) -Indol-1-yl] -pyrimidin-2- Amino } - Cyclohexanecarboxylic acid methyl  Ester

1- (2-Chloro-pyrimidin-4-yl) -4- (3-methanesulfonyl-propoxy) -1H-indole (300 g), 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (155 g ) And K ₂ CO ₃ (170 g) in NMP (2.35 L) were stirred at 80 ° C. for 5 hours and then at room temperature overnight. The reaction mixture was then stirred in an ice bath and then slowly added water (2.5 L) with stirring and cooling continued until the exothermic reaction was complete. Upon cooling, the mixture is filtered and the resulting solid is rinsed with H ₂ O and dried overnight in vacuo to afford 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl] -pyrimidine 2-ylamino} -cyclohexanecarboxylic acid methyl ester (97%) was obtained.

Example  15: 4- {4- [4- (3- Methanesulfonyl - Propoxy ) -Indol-1-yl] -pyrimidin-2- Amino } - Cyclohexanecarboxylate Sodium salt

An aqueous solution of NaOH (50% (w / w)) in H ₂ O (198.95 g) was added with 4- {4- [4- (3-methanesulfonyl-propoxy) -indole-1- in IPA (7.5 L). Was added to yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid methyl ester (830.0 g), and the mixture was stirred at 82 ° C. for 1 hour and then at room temperature overnight. The mixture is then filtered, the solid is rinsed with IPA and dried in vacuo at 60 ° C. for 3 days to give sodium 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl]- Pyrimidin-2-ylamino} -cyclohexanecarboxylate (96.9%) was obtained.

Example  16: 4- (1,1- Dioxo - Tetrahydro -1λ ^* 6 ^* -Thiophene-3- Ylmethoxy ) -1- (2-pro Lofilsulfa Nyl-pyrimidin-4-yl) -1H-indole

1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indol-4-ol (1.56 g) and toluene-4-sulfonic acid 1,1-dioxo-tetrahydro-1λ ^* 6 ^* - Thiophen-3-ylmethyl ester (2.37 g) was added to NMP (20 mL), followed by cesium carbonate (5.08 g). The mixture was stirred at 70 ° C. for 60 hours and then the solvent was removed by distillation. The residue was diluted with HCl (IN) and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford 2.96 g of 4- (1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophen-3-ylmethoxy ) -1- (2-propylsulfanyl-pyrimidin-4-yl) -1H-indole was obtained.

Example  17: 4- (1,1- Dioxo - Tetrahydro -1λ ^* 6 ^* -Thiophene-3- Ylmethoxy ) -1- [2- (propane-1- Sulfinyl ) -Pyrimidin-4-yl] -1H-indole

4- (1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophen-3-ylmethoxy) -1- (2-propylsulfanyl-pyrimidin-4-yl) in methylene chloride (40 mL) The solution of -1H-indole (1.16 g) was cooled to 0 ° C and meta-perchloro benzoic acid (3.58 g) was added. The mixture was stirred for 45 minutes and then quenched by addition of saturated aqueous NaHCO ₃ . The mixture was extracted with methylene chloride, the combined organic layers were dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give 1.2 g of 4- (1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophen-3 -Ylmethoxy) -1- [2- (propane-1-sulfinyl) -pyrimidin-4-yl] -1H-indole was obtained.

Example  18: 4- {4- [4- (1,1- Dioxo - Tetrahydro -1λ ^* 6 ^* -Thiophene-3- Ylmethoxy ) -Indol-1-yl] -pyrimidin-2- Amino } - Cyclohexanecarboxylic acid  Ethyl ester

4- (1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophen-3-ylmethoxy) -1- [2- (propane-1-sulfinyl) -pyrimidine- in NMP (5 mL) Diisopropylethylamine (1.4 mL) was added to a solution of 4-yl] -1H-indole (1.2 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (1.12 g). The mixture was heated to 80 ° C. for 18 h, then cooled and poured into water (75 mL). The mixture was extracted with methylene chloride and the combined organic layers were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexane) to give 1.069 g of 4- {4- [4- (1,1-dioxo-tetrahydro-1λ ^* 6 ^* -thiophen-3-ylmethoxy) -Indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ethyl ester was obtained.

Example  19: 4- {4- [4- (3- Methanesulfonyl - Propoxy ) -Indol-1-yl] -pyrimidin-2- Amino } - Cyclohexanecarboxylate Sodium salt

An aqueous solution of NaOH (50% (w / w)) in H ₂ O (198.95 g) was added with 4- {4- [4- (3-methanesulfonyl-propoxy) -indole-1- in IPA (7.5 L). Was added to yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid methyl ester (830.0 g), and the mixture was stirred at 82 ° C. for 1 hour and then at room temperature overnight. The mixture is then filtered, the solid is rinsed with IPA and dried in vacuo at 60 ° C. for 3 days to give sodium 4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl]- Pyrimidin-2-ylamino} -cyclohexanecarboxylate (96.9%) was obtained.

Example 20: (R) -1- (4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-yl army furnace}- Cyclohexanecarbonyl ) -Piperidine-3- Carboxylic acid  Ethyl ester

Sodium 4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylate (0.4 g), (R) -P Ferridine-3-carboxylic acid ethyl ester (0.165 g), BOP (0.537 g) and DIPEA (0.56 mL) were added to DMF (3 mL) and the mixture was stirred at rt overnight. The mixture was diluted with water and the resulting precipitate collected by filtration, washed with water, dried under reduced pressure and purified by flash chromatography (DCM / MeOH) to give 39.6 mg of (R) -1- (4- {4- [ 4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarbonyl) -piperidine-3-carboxylic acid ethyl ester was obtained. Melting point = 175.0 to 177.0 ° C.

Additional compounds prepared using this procedure are shown in Table 1.

Biological analysis

Example  21: In vitro JNK  analysis

JNK activity was measured by phosphorylation of GST-ATF2 (19-96) using [γ- ³³ P] ATP. 40 μL final in buffer containing 25 mM HEPES, pH 7.5, 2 mM dithiothreitol, 150 mM NaCl, 20 mM MgCl ₂ , 0.001% Tween® 20, 0.1% BSA and 10% DMSO In volume, enzymatic reactions were performed at substrate and Km concentrations of ATP. Human JNK2α2 assay contained 1 nM enzyme, 1 μM ATF2, 8 μM ATP with 1 μCi [γ- ³³ P] ATP. Human JNK1α1 assay contained 2 nM enzyme, 1 μM ATF2, 6 μM ATP with 1 μCi [γ- ³³ P] ATP. Human JNK3 (Upstate Biotech # 14-501M) assay contained 2 nM enzyme, 1 μM ATF2, 4 μM ATP with 1 μCi [γ- ³³ P] ATP. Enzyme analysis was performed in the presence or absence of several compound concentrations. JNK and the compound were preincubated for 10 minutes, followed by the addition of ATP and substrate to initiate the enzyme reaction. The reaction mixture was incubated at 30 ° C. for 30 minutes. At the end of the incubation, 25 μL of the reaction mixture was transferred to 150 μL of 10% glutathione Sepharose® slurry (Amersham # 27-4574-01) containing 135 mM EDTA and reacted. Was terminated. The reaction product was captured on an affinity resin and washed six times with phosphate buffered saline on a filtration plate (Millipore, MABVNOB50) to remove the free radionucleotides. The incorporation of ³³ P into ATF2 was quantified on a microplate scintillation counter (Packard Topcount). Compound inhibition efficacy for JNK was determined by IC ₅₀ values generated from 10 concentration inhibition curves fitted with a 3-variable model:% inhibition = maximum / (1+ (IC ₅₀ / [inhibitor]) ^slope ). Data were analyzed with Microsoft Excel for parameter estimation. Representative results are shown in Table 1 above.

Example  22: Rat  In vivo TNF α-derived IL -6 generation analysis

Female Wistar-Han rats obtained from Charles River Laboratories were acclimated for 1 week prior to use and allowed to achieve a body weight of approximately 101-130 g. Test compounds (N = 8 / compound) were administered to rats via oral gavage, and 30 min later inoculated with 0.5 μg of recombinant rat TNF-α (Biosource). 90 minutes after TNF-α inoculation, blood was collected through cardiac puncture. Plasma was prepared using a lithium heparin separation tube (BD microtainer) and frozen at −80 ° C. until analysis. IL-6 levels were determined using a rat specific IL-6 ELISA kit (BioSource). The percent inhibition and the ED ₅₀ value (calculated as the dose of compound at the point where TNF-α production is 50% of the control value) were determined.

Example  23: Rat  In vivo TNF α-derived IL -6 generation analysis

Female Wistar-Han rats obtained from Charles River Laboratories were allowed to acclimate for 1 week prior to use and achieve a body weight of approximately 114-132 g. Test compounds (N = 8 / dose) were administered to rats via subcutaneous injection and 30 min later inoculated with 0.5 μg of recombinant rat TNF-α (biosource) intraperitoneally. 90 minutes after TNF-α inoculation, blood was collected through cardiac puncture. Plasma was prepared using a lithium heparin separation tube (BD microtainer) and frozen at −80 ° C. until analysis. IL-6 levels were determined using a rat specific IL-6 ELISA kit (BioSource). The percent inhibition and the ED ₅₀ value (calculated as the dose of the compound at the point where TNF-α production is 50% of the control value) were determined.

Example  24: Rodent Collagen-Induced Arthritis

Seven to eight weeks old female Lewis rats obtained from Harlan Laboratories were acclimated for one week before use and allowed to achieve a weight of approximately 120-140 g. On the day of the test, an emulsion of 100 μg bovine type II collagen (Chondrex) in Incomplete Freund's adjuvant (IFA) was used to subcutaneously firstly derive some areas of the back of the rat (IFA; 0.1 ml total at 2-3 sites). Arthritis induction is generally observed 12-14 days after the first sensitization, but on approximately 7-10 days, a boosted injection of 100 μg collagen / IFA is administered to the bottom of the tail or to another site (such as intradermal to 0.1 ml or less). Administration) induced disease at the same time. Compound administration can be prophylactic (starting at additional administration or one to two days before) or therapeutic (starting after additional administration and at an initial disease score of 1-2; see clinical scoring below). Over the next 21 days, the development and progression of the disease in the animals was evaluated.

Rats were evaluated by using a scoring system (described below), using a volumetric flow meter to measure foot volume for each foot, or measuring foot or joint thickness with a caliper. Baseline measurements were performed no more than three times per week on the test day and from the first signs of edema and until the end of the experiment. Scoring was evaluated as follows for each foot:

1 = edema and / or redness of one foot or toe.

2 = edema in more than one joint.

3 = severe edema of the foot with more than two joints.

4 = severe arthritis of the entire foot and toes.

Arthritis index for each rat was assessed by adding four scores of each foot and giving a maximum score of 16. In order to continuously measure disease incidence and progression, hind paw volume was also measured using a volumetric flow meter.

At the end of the study, gravimetric, histological, cellular and / or molecular analysis of hind paws (and other tissues) was performed. Blood was collected via cardiac puncture and plasma was prepared using lithium heparin separation tubes (BD microtainers) and frozen at −70 ° C. until analysis. Inflammatory cytokine levels (eg, TNF-α, IL-1 and IL-6) from plasma or homologous joint tissues were determined using a rat specific ELISA kit (R & D). As a combination of changes in clinical score, paw volume and histopathology, the level of disease protection or inhibition was determined in comparison to control animals.

Example  25: Rat  Pharmacokinetic study

Female Wistar / Han (CRL: WI) rats (Higgs River, Hollister, CA) of 180-220 g body weight were used. Animals were given free access to standard laboratory feed and tap water and housed in a constant temperature-humidity environment. Single 10 mg / kg IV bolus dose (50%) prepared in an aqueous vehicle containing 0.9% NaCl, 0.5% sodium carboxymethyl cellulose, 0.4% polysorbate 80 and 0.9% benzyl alcohol in three rats per dosing regimen Cyclodextran / water) or a single 10 mg / kg oral suspension dose. Blood was collected from each rat anesthetized with CO ₂ : O ₂ (60:40) via orbital pulsation or cardiac puncture at 1, 3, 6, 8 and 24 hours post dose. Plasma levels of test compounds were analyzed by LC / MS method. In this method, aliquots of plasma were treated by mixing with acetonitrile to precipitate the protein, centrifuged to make the supernatant clear, then further diluted with foamate buffer (50 mM) and injected by HPLC. Test compounds were separated from endogenous interferences and then eluted from HPLC columns for mass spectrometry.

While the invention has been described with reference to specific embodiments, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, ingredient composition, process, process step, to the spirit and scope of the purposes of the present invention. All such modifications are intended to be within the scope of the appended claims.

Claims (24)

Claims 1. Compounds of the general formula < RTI ID = 0.0 > (I) < / RTI &
Formula I

In this formula,
m is 0 to 2;
n is 0 to 2;
p is 0 to 3;
X is CH or N;
R ¹ is each independently hydrogen or C _{1 - 6} alkyl, and;
R ² are each independently C _{1 - 6} alkyl, C _{1 - 6} alkoxy halo -C _{1 - 6} alkyl or halo -C _{1 - 6} alkoxy;
R ³ is C _{1 - 6} alkylsulfonyl -C _{1 - 6} alkyl, tetrahydro-thiophenyl-1,1-oxide, -C _{1 - 6} alkyl, or tetrahydro-thiopyran-1,1-oxide, -C _{1 - 6} alkyl ego;
R ⁴ are each independently C _{1 - 6} alkyl, C _{1 - 6} alkoxy halo -C _{1 - 6} alkyl or halo -C _{1 - 6} alkoxy;
R ⁵ is a group of formula a or b:
A

Formula b

q is 0 or 1;
r is 0 or 1;
Y is NR ⁹ or CR ¹⁰ R ¹¹ ;
R ⁶ and R ⁷ are each independently hydrogen, carboxy, carboxy -C _{1 - 6} alkyl ester or C _{1 - 6} alkyl; R ⁶ and R ⁷ together are C _{1 -} to form a ₂ alkylene;
R ⁸ is hydrogen or C _{1 - 6} alkyl, and;
R ⁹ is hydrogen or C _{1 - 6} alkyl, and;
R ¹⁰ is hydrogen or C _{1 - 6} alkyl, and;
R ¹¹ is hydrogen, C _{1 - 6 alkoxy, NH 2 C (O) -} , C 1 - 6 alkyl, hydroxy -C _{1 - 6} alkyl, carboxy, carboxy -C _{1 - 6} alkyl, carboxy -C _{1 - 6} alkyl ester or a carboxy -C _{1 - 6} alkyl, C _{1 - 6} alkyl ester. The method of claim 1,
m is 0 to 2;
n is 0 to 2;
p is 0 to 3;
X is CH or N;
R ¹ is each independently hydrogen or C _{1 - 6} alkyl, and;
R ² are each independently C _{1 - 6} alkyl, C _{1 - 6} alkoxy halo -C _{1 - 6} alkyl or halo -C _{1 - 6} alkoxy;
R ³ is C _{1 - 6} alkylsulfonyl -C _{1 - 6} alkyl, thiophenyl-1,1-oxide, -C _{1 - 6} alkyl, or tetrahydro-thiopyran-1,1-oxide, -C _{1 - 6} alkyl;
R ⁴ is each independently C _{1 - 6} alkyl, C _{1 - 6} alkoxy halo -C _{1 - 6} alkyl or halo -C _{1 - 6} alkoxy;
R ⁵ is a group of formula a or b:
A

Formula b

q is 0 or 1;
r is 0 or 1;
Y is NR ⁹ or CR ¹⁰ R ¹¹ ;
R ⁶ and R ⁷ are each independently hydrogen or C _{1 - 6} alkyl; To form a _{2-alkylene -} R ⁶ and R ⁷ together are C _1;
R ⁸ is hydrogen or C _{1 - 6} alkyl, and;
R ⁹ is hydrogen or C _{1 - 6} alkyl, and;
R ¹⁰ is hydrogen or C _{1 - 6} alkyl, and;
R ¹¹ is C _{1 - 6} alkyl, hydroxy -C _{1 - 6} alkyl, carboxy, carboxy -C _{1 - 6} alkyl, carboxy -C _{1 - 6} alkyl ester or carboxy -C _{1 - 6} alkyl, C _{1 - 6} alkyl ester
/ RTI > 3. The method according to claim 1 or 2,
m is 0. The method according to any one of claims 1 to 3,
wherein n is 0. The method according to any one of claims 1 to 4,
p is zero. 6. The method according to any one of claims 1 to 5,
the compound of q is one. 6. The method according to any one of claims 1 to 5,
and q is 0. The method according to any one of claims 1 to 7,
X is CH. The method according to any one of claims 1 to 7,
X is N. 10. The method according to any one of claims 1 to 9,
Y is NR ⁹ . 10. The method according to any one of claims 1 to 9,
Y is CR ¹⁰ R ¹¹ . 12. The method according to any one of claims 1 to 11,
R ³ is C _{1 - 6} alkylsulfonyl -C _{1 - 6} alkyl. 12. The method according to any one of claims 1 to 11,
R ³ is tetrahydro-thiophenyl-1,1-oxide, -C _{1 - 6} alkyl. 14. The method according to any one of claims 1 to 13,
R ⁵ is a group of formula a. 14. The method according to any one of claims 1 to 13,
R ⁵ is a group of formula b. The method of claim 1,
[1- (4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarbonyl) -piperidine-4 -Yl] -acetic acid ethyl ester;
(R) -1- (4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarbonyl) -piperi Dine-3-carboxylic acid ethyl ester;
(4- {4- [4- (1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexyl )-((R) -4-ethyl-3-methyl-piperazin-1-yl) -methanone;
(S) -1- (4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarbonyl) -piperi Dine-3-carboxylic acid;
1- (4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarbonyl) -piperidine-4- Carboxylic acid amides;
[4- (1-Hydroxy-1-methyl-ethyl) -piperidin-1-yl]-(4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl ] -Pyrimidin-2-ylamino} -cyclohexyl) -methanone;
1- (4- {4- [4- (1,1-Dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethoxy) -indol-1-yl] -pyrimidin-2-ylamino}- Cyclohexanecarbonyl) -piperidine-4-carboxylic acid ethyl ester;
1- (4- {4- [4- (1,1-Dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethoxy) -indol-1-yl] -pyrimidin-2-ylamino}- Cyclohexanecarbonyl) -piperidine-4-carboxylic acid;
(4- {4- [4- (1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexyl )-((S) -4-ethyl-3-methyl-piperazin-1-yl) -methanone;
1- (4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarbonyl) -4-methyl-piperi Dine-4-carboxylic acid ethyl ester;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((R) -1-propyl-pyrrolidine -3-yl) -amide;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((R) -1-ethyl-pyrrolidine -3-yl) -amide;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((S) -1-ethyl-pyrrolidine -3-yl) -amide;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((R) -1-propyl-piperidine -3-yl) -amide;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((R) -1-ethyl-piperidine -3-yl) -amide;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((S) -1-propyl-piperidine -3-yl) -amide;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((S) -1-ethyl-piperidine -3-yl) -amide;
1- (4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarbonyl) -4-methyl-piperi Dine-4-carboxylic acid;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid methyl- (1-methyl-piperidine-2 -Ylmethyl) -amide;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid (1-ethyl-pyrrolidin-2-yl Methyl) -amide;
(1R, 4S) -2,5-Diaza-bicyclo [2.2.1] hept-2-yl- (4- {4- [4- (3-methanesulfonyl-propoxy) -indole-1- Yl] -pyrimidin-2-ylamino} -cyclohexyl) -methanone;
(4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexyl)-(8-methyl-3,8-dia Za-bicyclo [3.2.1] oct-3-yl) -methanone;
(4- {4- [4- (3-Methanesulfonyl-propoxy) -indazol-1-yl] -pyrimidin-2-ylamino} -cyclohexyl)-((S) -3-methyl- Piperazin-1-yl) -methanone;
(4- {4- [4- (3-Methanesulfonyl-propoxy) -indazol-1-yl] -pyrimidin-2-ylamino} -cyclohexyl)-((R) -3-methyl- Piperazin-1-yl) -methanone;
(4- {4- [4- (1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethoxy) -indazol-1-yl] -pyrimidin-2-ylamino} -cyclo Hexyl)-((S) -3-methyl-piperazin-1-yl) -methanone;
(3-ethoxy-8-aza-bicyclo [3.2.1] oct-8-yl)-(4- {4- [4- (3-methanesulfonyl-propoxy) -indol-1-yl] -Pyrimidin-2-ylamino} -cyclohexyl) -methanone;
(4- {4- [4- (1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethoxy) -indazol-1-yl] -pyrimidin-2-ylamino} -cyclo Hexyl)-((S) -3-methyl-piperazin-1-yl) -methanone;
(3,3-Dimethyl-piperazin-1-yl)-(4- {4- [4- (1,1-dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethoxy) -indole- 1-yl] -pyrimidin-2-ylamino} -cyclohexyl) -methanone;
4- {4- [4- (1,1-Dioxo-tetrahydro-1λ ⁶ -thiophen-3-ylmethoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid (1-ethyl-piperidin-3-yl) -amide;
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((S) -1-ethyl-pyrrolidine -2-ylmethyl) -amide; And
4- {4- [4- (3-Methanesulfonyl-propoxy) -indol-1-yl] -pyrimidin-2-ylamino} -cyclohexanecarboxylic acid ((R) -1-ethyl-pyrrolidine -2-ylmethyl) -amide
≪ / RTI > A method of treating a JNK-mediated disorder in a subject with a JNK-mediated disorder comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 16 to a subject in need thereof. The method of claim 17,
The arthritis is rheumatoid arthritis. The method of claim 17,
JNK-mediated disorder is asthma. The method of claim 17,
JNK-mediated disorder is diabetes. A composition comprising a compound according to any one of claims 1 to 16 and at least one pharmaceutically acceptable carrier, excipient or diluent. Use of a compound according to any one of claims 1 to 16 in the manufacture of a medicament for the treatment of an inflammatory disorder. 17. The method according to any one of claims 1 to 16,
Compounds for use in the treatment of inflammatory disorders. The invention as described above.